Vaccinesbased immunotherapy

Sipuleucel-T is an active cellular immunotherapy consisting of autologous peripheral-blood mononuclear cells, including antigen-presenting cells (APCs), which have been activated ex vivo with a recombinant fusion protein known as PA2024, composed of prostatic acid phos-phatase (PAP) linked to granulocyte-macrophage colony-stimulating factor (GM-CSF). In the first two randomized trials, sipuleucel-T, the primary endpoint was not accomplished since these studies did not show a significant effect on the time to disease progression comparing with placebo. Despite this, the hazard ratios were in favor of sipuleucel-T [66, 67]. The IMPACT trial, a phase III trial in CPRC asyntomatic patients, resulted in a longer median survival time in the Sipuleucel-T group, with limited toxicity. Approved by the Food and Drugs Administration (FDA), currently Sipuleucel-T is not approved to been used in Europe [68].

GVAX (CGI940/CG8711] is a cellular vaccine composed of two allogeneic prostate cancer cell lines (LNCaP and PC-3] that is genetically modified to secrete GM-CSF [69]. This vaccine showed clinical benefit with limited toxicity in phase I and II trials [70, 71]. However, the two phase III trials (VITAL-1 and VITAL-2] evaluated GVAX against docetaxel plus pre-dnisone in nai've CRPC and both were closed prematurely [70]. The VITAL-1 study was closed when the unplanned futility analysis revealed a <30% chance of meeting its predefined primary endpoint of OS improvement and the VITAL-2 terminated when an interim analysis revealed more deaths in the GVAX arm than in the control [71].

PROSTVAC-VF is a cancer vaccine consisting of a recombinant vaccinia vector as a priming immunization with subsequent multiple booster vaccinations, using a recombinant fowlpox vector. This agent presented in the context of 3 costimulatory molecules (ICAM-1, BLA-7, and LFA-3] which, when taken together, demonstrate an increase in strength of the target immuno-logic response [48]. This vaccine was evaluated in phase I and II trials. The phase I trial showed PSA stabilization in 40% of patients and limited toxicity and, in the phase II study, patients in the PROSTVAC-VF arm achieved an 8.5-month improvement in median OS [25.1 months versus 16.6 months) and a 44% reduction in the death rate (Hazard ratio 0.56], [72]. Phase III trial are being planned and other vaccines are under current development [73].

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